Systemic lupus erythematosus (SLE) is a complex, prototypic, systemic autoimmune disease of great interest to the Autoimmunity Center of Excellence network. However, by the time patients receive the devastating SLE diagnosis, the majority have ongoing aggressive inflammatory processes and oftentimes damage that cannot be reversed. Once these autoimmune cascades are underway, dissecting the basic concepts of disease initiation, perpetuation and direct pathogenesis from the complications of end-organ damage can be quite difficult. Our Oklahoma ACE builds on unique populations and experimental systems to address early events in systemic autoimmunity. Few repositories exist that allow researchers to investigate SLE development before clinical manifestations. Through our collaboration with the US Department of Defense, we have identified 240 patients who developed SLE while serving in the US military and who had serum samples that were provided before SLE classification. We previously obtained serial samples from the DoDSR for 130 of these patients, as well as four matched controls for each patient. Initial studies with these samples found that autoantibodies precede clinical illness by many years, that the Sm and Ro (alone) systems begin by targeting a single antigenic structure then become progressively more complicated and that a few autoantibodies are detectable before their associated clinical manifestations. In addition, we now have in house the samples from an additional 100 SLE patients and their matched controls and are seeking ACE funding to examine temporal associations of key targetable pathways in the pre-clinical stages to support or refute rationale use of interventions directed against interferon alpha or vitamin D supplementation for SLE patients. Further elucidation of the etiology and early pathogenesis of SLE will also provide improved biomarkers regarding select aspects of autoantibodies that correlate with onset of clinical disease features, and identify autoantibody subsets that help predict disease and allow identification of high risk populations for potential interventional trials. Our specific aims will address the following key clinical questions: 1) Does vitamin D deficiency precede lupus autoimmunity and/or clinical disease onset? 2) Does an increase in interferon activity occur before or concurrently with the onset of lupus autoimmunity or clinical disease? 3) Does non-specific autoimmunity precede onset of lupus-specific autoimmunity and thereby serve as a predictor of disease? 4) Does autoantibody concentration, specificity or affinity change with symptom onset and can these changes help direct therapeutic decisions?